Li Jiang, Shilin Yang, Huiyong Yin, Xiaofeng Fan, Suwan Wang, Bing Yao, Ambra Pozzi, Xiaoping Chen, Raymond C. Harris, and Ming-Zhi Zhang
Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11beta-hydroxysteroid dehydrogenase type II (11ßbetaHSD2)-mediated metabolism. We previously reported that 11betaHSD2 increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity, and 11betaHSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. 11betaHSD2 is expressed in Apc+/min mouse intestinal adenoma stromal and epithelial cells. We generated Apc+/min mice with selective deletion of 11betaHSD2 in intestinal epithelial cells (Vil-HSD2-/- Apc+/min). 11betaHSD2 deletion in intestinal epithelia led to marked inhibition of Apc+/min mouse intestinal tumorigenesis. Immunostaining indicated decreased 11ßHSD2 and COX-2 expression in adenoma epithelia, while stromal COX-2 expression was intact in Vil-HSD2-/- Apc+/min mice. In Vil-HSD2-/- Apc+/min mouse intestinal adenomas, both p53 and p21 mRNA and protein levels were increased, with concomitant decrease in phosphorylation of retinoblastoma protein, indicating glucocorticoid-mediated G1 cell cycle arrest. Regulated in development and DNA damage responses 1 (REDD1), a novel stress-induced gene that inhibits mammalian target of rapamycin (mTOR) signaling pathway, was increased, while the mTOR signaling pathway was inhibited. Therefore, in Vil-HSD2-/- Apc+/min mice, epithelial cell 11betaHSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased G1 cell cycle arrest and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. 11betaHSD2 inhibition may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways.